1. Field of the Invention
The present invention relates to a therapeutic formulation which is utilized with percutaneous absorption.
More particularly, the present invention relates to a transdermal therapeutic formulation which is excellent in both of percutaneous absorption and safety, capable of delivering desired pharmaceutically active substances rapidly to a desired location of treatment or to the whole parts of the body through the circulating system and thus effective for curing various kinds of disease.
2. Prior Art
During the recent progress of medical treatment, transdermal therapeutic systems(TTS) have been developed. In these systems, desired pharmaceutical substances are absorbed percutaneously and delivered to the whole parts of the body and thus the curing effect can be maintained for a prolonged time. For example, systems which are practiced recently utilize, as the pharmaceutically active substances, drugs for angina pectoris, such as nitroglycerin and isosorbide dinitrate, drugs for hypertonia, such as clonidine and drugs for climacteric difficulties, such as estradiol.
However, even though these transdermal therapeutic systems show many advantages such as evasion of metabolism of the pharmaceutically active substances at the intestine and liver, reduction of side reactions and increased maintenance of the pharmaceutical effect, they have defects that, because skin essentially has the barrier function against invasion of foreign substances, only limited kinds of pharmaceutically active substances can attain the concentration of the substances in blood high enough to show the pharmaceutical effect and the pharmaceutically active substances which can be utilized for the systems are naturally very limited.
Various methods have been tried so far to improve the percutaneous absorption of the pharmaceutically active substances. For example, pharmaceutically active substances were modified to form prodrugs and complexes and ionic pharmaceutically active substances were utilized in connection with ion tophoresis. These methods have a problem that the actual application requires detailed studies on the individual pharmaceutically active substance and a long period of time and a large amount of investment are inevitably required. On the other hand, development of percutaneous absorption promoters which increase percutaneous absorption of pharmaceutically active substances by decreasing the barrier property of skin has been actively made. It is expected that, by the use of these absorption promoters, various kinds of pharmaceutically active substances can be utilized without much limitation.
Examples of such percutaneous absorption promoters are polar solvents such as dimethyl sulfoxide, decyl methyl sulfoxide, dimethyl formamide, dimethyl acetamide and the like, cycloalkanes such as 1-dodecylazacycloheptan-2-one and the like, esters of alcohols and carboxylic acids such as isopropyl myristate, isopropyl palmitate and the like, surface active agents such as glycols, sodium lauryl sulfate and the like and derivatives of natural moisturizing factors of skin such as fatty acids, pyroglutamic acid, urea and the like. However, these absorption promoters cannot always satisfy both of the requirements on percutaneous absorption promotion and the requirements on safety. Furthermore, many of the promoters have a problem that the lag time of a drug absorption is considerably long and it takes a long time before the desired pharmaceutical effect is actually exhibited.